Sadanaga Atsushi, Nakashima Hitoshi, Akahoshi Mitsuteru, Masutani Kohsuke, Miyake Katsuhisa, Igawa Takashi, Sugiyama Naonobu, Niiro Hiroaki, Harada Mine
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Arthritis Rheum. 2007 May;56(5):1618-28. doi: 10.1002/art.22571.
To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis.
MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/lpr mice intraperitoneally with either poly(I-C) (50 or 100 microg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters.
In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti-double-stranded DNA (anti-dsDNA) and production of cytokines, including interferon-alpha (IFNalpha), interleukin-12 (IL-12), IL-6, and IFNgamma, in splenocytes were significantly reduced in MyD88-KO MRL/lpr mice. Interestingly, MyD88-KO MRL/lpr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes.
The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.
确定固有受体信号在MRL/lpr小鼠（一种狼疮性肾炎实验模型）自身免疫性肾炎的发展中是否起重要作用。
髓样分化因子88（MyD88）是一种关键衔接蛋白，参与除Toll样受体3（TLR-3）外的所有Toll样受体（TLR）信号通路。因此，我们培育了MyD88基因敲除（MyD88-KO）的MRL/lpr小鼠，并检查其肾脏的组织病理学变化、累积生存率、淋巴结病和脾肿大程度、血清化学指标以及免疫参数。此外，为了明确MyD88非依赖途径在自身免疫性肾炎中的作用，我们给MyD88-KO MRL/lpr小鼠腹腔注射聚肌苷酸-聚胞苷酸（poly(I-C)）（每只小鼠50或100微克）或磷酸盐缓冲盐水，并检查其生存率以及组织病理学、血清学和免疫参数。
与野生型小鼠相比，MyD88-KO MRL/lpr小鼠寿命延长，未出现明显的自身免疫性肾炎。其肾脏未显示肾小球细胞增殖或新月体形成，同时系膜基质大幅减少。淋巴结病和脾肿大不太明显。MyD88-KO MRL/lpr小鼠的抗双链DNA（抗dsDNA）血清滴度以及脾细胞中包括干扰素-α（IFNα）、白细胞介素-12（IL-12）、IL-6和干扰素-γ（IFNγ）在内的细胞因子产生均显著降低。有趣的是，用MyD88非依赖的TLR-3配体poly(I-C)处理的MyD88-KO MRL/lpr小鼠几乎完全恢复为野生型小鼠的特征，表现为新月体性肾小球肾炎，血清抗dsDNA滴度显著升高，脾细胞中细胞因子产生增加。
研究结果表明，MyD88依赖和MyD88非依赖的固有信号在MRL/lpr小鼠自身免疫性肾炎的发展中均起关键作用。
